Voltage-dependent calcium channels are ion channels that cause influx of calcium ions into cells under the potential difference between the interior and the exterior of a cell, and are known to have important biological functions, including neuronal excitation, synaptic transmission, muscle contraction, cardiac automaticity, secretion of neurotransmitters and hormones, cell proliferation and differentiation, and the like. Voltage-dependent calcium channels have been classified into any of the five categories T, L, P/Q, N, and R by their electrophysiological and pharmacological properties [Physiological Review, Vol. 83, p. 117 (2003)]. Among these five channels, only the T-type channels are activated by high membrane potentials, and are called low-voltage-activated channels. The other four channels are called high-voltage-activated (hereinafter, “HVA”) channels, because of their activation at low membrane potentials. As the name suggests, the T (transient)-type calcium channels are characterized by transient activation and quick inactivation. On the other hand, the HVA channels require a long time for inactivation.
It is known that the HVA channels basically act as a heterotetramer having α1, α2/δ, β, and γ subunits. It is known that, among these subunits, the α1 subunit is the subunit that forms a channel pore, whereas the other subunits act as regulatory or accessory subunits. On the other hand, it is believed that the T-type calcium channels act as the α1 subunit alone. Currently, ten kinds of α1 subunits are known in voltage-dependent calcium channels, and three of these α1 subunits, α1G (Cav3.1), α1H (Cav3.2), and α1I (Cav3.3) are known to form the T-type calcium channels.
The expression of T-type calcium channels has been confirmed in the peripheral and central nervous systems, heart, kidneys, smooth muscle, skeletal muscle, endocrine cells, bone, sperm, and the like. As physiological functions of the T-type calcium channels, neuronal firing, sleeping, pain transmission, heart's pacemaker function, renovascular tonus, hormone secretion, fertilization, and the like, are reported [Physiological Review, Vol. 83, p. 117 (2003); Trends in Pharmacological Science, Vol. 30, p. 32 (2008); Proceedings of the National Academy of Science of the United States of America, Vol. 102, p. 1743 (2005); Proceedings of the National Academy of Science of the United States of America, Vol. 101, p. 18195 (2004)].
As a disease associated with enhancement of the T-type calcium channels, epilepsy [Neuron, Vol. 31, p. 35 (2001); Annals of Neurology, Vol. 54, p. 239 (2003); Journal of Neurophysiology, Vol. 98, p. 2274 (2007)], pain [Channels, Vol. 1, p. 238 (2007); EMBO Journal, Vol. 24, p. 315 (2005); Journal of Neuroscience, Vol. 27, p. 3305 (2007); Molecular Cells, Vol. 25, p. 242 (2008); Acta Pharamacologica Sinica, Vol. 27, p. 1547 (2006); Genes, Brain and Behavior, Vol. 6, p. 425 (2007); Pain, Vol. 105, p. 159 (2003); Pain, Vol. 109, p. 150 (2004); Pain, Vol. 145, p. 184 (2009)], heart disease [Journal of Pharmacological Sciences, Vol. 99, p. 197 (2005); Journal of Pharmacological Sciences, Vol. 99, p. 205 (2005); Journal of Pharmacological Sciences, Vol. 99, p. 211 (2005); Journal of Pharmacological Sciences, Vol. 99, p. 214 (2005)], kidney disease [American Journal of Kidney Disease, Vol. 38, p. 1241 (2001); Journal of Pharmacological Science, Vol. 99, p. 221 (2005); Circulation Research, Vol. 100, p. 342 (2007)], inflammation and edema [Pharmacological Research, Vol. 44, p. 527 (2001)], arteriosclerosis [Cardiology, Vol. 89, p. 10 (1998)], aldosteronism [The Journal of Pharmacology and Experimental Therapeutics, Vol. 287, p. 824 (1998)], cancer [Cell Calcium, Vol. 36, p. 489 (2004); Molecular Pharmacology, Vol. 62, p. 210 (2002)], hearing impairment [Hearing Research, Vol. 226, p. 52 (2007)], and the like, have been reported. T-type calcium channel antagonists are thus considered effective for the treatment or prevention of these diseases. In fact, the cardioprotective effect [Circulation Journal, Vol. 67, p. 139-145 (2003); Circulation, Vol. 101, p. 758 (2000)] and the renoprotective effect [Hypertension Research, Vol. 30, p. 621 (2007)] of T-type calcium channel antagonists are reported in the clinic. Further, it was reported that T-type calcium channels are involved in sleeping [Proceedings of the National Academy of Science of the United States of America, Vol. 102, p. 1743 (2005); Proceedings of the National Academy of Science of the United States of America, Vol. 101, p. 18195 (2004)], and their antagonists may be effective for the treatment and/or prevention of sleep disorder [Current Opinion in Pharmacology, Vol. 8, p. 33 (2008)]. Further, in recent years, it was reported that T-type calcium channel antagonists may be effective for the treatment and/or prevention of pruritus (WO2010/110428).
Among the compounds that act on the T-type calcium channels, many compounds are known as a T-type calcium channel inhibitor. Examples include efonidipine (see, Non-Patent Documents 1 and 2, and the like), mibefradil (see, Non-Patent Document 3, and the like), diphenylmethane derivatives (see, Patent Document 1, and the like), dihydroquinazoline derivatives (see, Patent Documents 2 and 3, and the like), piperidine derivatives (see, Patent Document 4, and the like), piperazine derivatives (see, Patent Document 5, and the like), azetidine and azetidone derivatives (see, Patent Document 6, and the like), thiazole derivatives (see, Patent Document 7, and the like), pyridine derivatives (see, Patent Document 8, and the like), and the like.
On the other hand, as a imidazopyridine derivative, compounds described in Patent Documents 9 to 38 and the like are known.
Furthermore, as a T-type calcium channel inhibitor, imidazopyridine derivatives and the like (see, Non-Patent Document 39) are known.